Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

• Published in: Cell death & disease Vol. 11; no. 9; p. 790
• Main Authors: Karvonen, Hanna, Arjama, Mariliina, Kaleva, Laura, Niininen, Wilhelmiina, Barker, Harlan, Koivisto-Korander, Riitta, Tapper, Johanna, Pakarinen, Päivi, Lassus, Heini, Loukovaara, Mikko, Bützow, Ralf, Kallioniemi, Olli, Murumägi, Astrid, Ungureanu, Daniela
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.09.2020
• Subjects: 13/89; 13/95; 14/34; 631/67/395; 631/67/71; 692/699/67/70; 82/29; 96/1; 96/106; 96/31; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Ovarian Epithelial - drug therapy; Carcinoma, Ovarian Epithelial - pathology; Cell Biology; Cell Culture; Cell Differentiation - drug effects; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Humans; Immunology; Life Sciences; Medicin och hälsovetenskap; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03009-4

Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.